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Membrane translocating peptide drug delivery system

Inactive Publication Date: 2007-09-11
MERRION RES I
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]MTLPs, MTLP-active agent complexes and MTLP-active particle complexes can be used alone, in combination with or conjugated to other molecules including, but not limited to, molecules that bind to target pathways, to nuclear uptake pathways and to endosomal pathways, molecules that enable mucoadhesion, molecules that facilitate diffusion across lipid membranes or through water filled pores and molecules that regulate or direct intra-cellular trafficking. That is, by using different mechanisms simultaneously, active agent bioavailability may be enhanced.
[0046]Another object of the present invention is to provide a method for treating a pathological disorder by oral administration of a MTLP-active particle complex, wherein the active particle contains a therapeutic agent such that the systemic concentration of the therapeutic agent is effective to treat the pathological disorder.

Problems solved by technology

However, these studies do not address the use of membrane translocating peptides to enhance active agent uptake into a cell, into and out of an intracellular compartment, or across a cell layer when the active agent is complexed to a membrane translocating peptide or when the active agent is incorporated into a particle and the particle is modified with (hereinafter, “complexed to”) a membrane translocating peptide.
Intravenous administration can result in adverse effects from rapid accumulation of high concentrations of drug, in patient discomfort and in infection at the injection site.
Intramuscular administration can cause pain at the injection site.
Subcutaneous administration is not suitable for large volumes or for irritating substances.
Although oral administration is the preferred route, many active agents are not absorbed efficiently across the GIT epithelium.

Method used

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  • Membrane translocating peptide drug delivery system
  • Membrane translocating peptide drug delivery system
  • Membrane translocating peptide drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

example 1

Peptide Synthesis

[0096]The membrane translocating peptides ZElan094, 204N and 204 and the targeting peptides HAX42, PAX2, P31 and Sni34 (U.S. patent applications Ser. Nos. 09 / 079,819, 09 / 079,723 and 09 / 079,678) were synthesized chemically using a fmoc synthesis protocol (Anaspec, Inc., San Jose, Calif.). A dansyl group was added at the N-terminus of each sequence in order to enable the detection of the peptide with anti-dansyl antibody (Table 3).

[0097]

TABLE 3MTLPs and targeting peptide sequencesSEQUENCEPEPTIDEZELAN NO:RECEPTORSEQ ID NO:H2N-K(dns)KKAAAVLLPVLLAAPMTLP09448MTLP-amideAAVLLPVLLAAKKKRKAMTLP204N23KKKRKAAAAVLLPVLLAMTLP20424H2N-K(dns)SDHALGTNLRSDNAK-HAX42011HPT149EPGDYNCCGNGNSTGRKVFNRRRSAIPYH2N-K(dns)PGDYNCCGNGNSTGHAX42091HPT150(14 mer)H2N-K(dns)LSTPPSREAYSRPYSV-PAX2055HPT151DSDSDTNAKHSSHNRRLRTRSRPNH2N-K(dns)Lys-TrKSSrSNPrGrrHPGP3110152(15 mer cyclic D form)H2N-K(dns)rtrlrrnhsshkantPAX2144RPT153(15 mer D form retroinversion)H2N-K(dns)TNAKHSSHNRRLRTRPAX2129HPT154H2N-K(dns)Lys-...

example 2

Preparation of MTLP-Active Particle Complexes and of Targeting Peptide-Active Particle Complexes

[0100]Active particles are prepared from a polymer using a coacervation method. Preferably, particle size is between about 5 nm and 750 μm, more preferably between about 10 nm and 500 μm and most preferably between about 50 nm and 800 nm. MTLPs or targeting peptides are complexed to the particles using various methods known to those skilled in the art.

[0101]The following is a general method for preparation of coacervated particles.

Phase A

[0102]A polymer agent, a surface-active agent, a surface-stabilizing agent, a surface-modifying agent or a surfactant is dissolved in water (A). Preferably the agent is a polyvinyl alcohol (hereinafter “PVA”) or a derivative thereof having a % hydrolysis of about 50-100 and a molecular weight range of about 500-500,000 kDa. More preferably the agent is a PVA having a % hydrolysis of 80-100 and a molecular weight range of about 10,000-150,000 kDa. The mixt...

example 3

Bovine Insulin Loaded-MTLP Coated Nanoparticles—MTLP Added in the Final Wash

[0110]Fast acting bovine insulin (28.1 IU / mg) was incorporated into polylactide-co-glycolide (PLGA, Boehringer Ingelheim, Indianapolis, Ind.) at a theoretical loading of 300 IU of insulin / 210 mg of nanoparticles and the nanoparticles were coated with the dansylated ZElan094 (SEQ ID NO: 48).

[0111]

COMPONENTAMMOUNTPLGA RG504H (Lot # 250583) 2 gAcetone 45 mlsEthanol 5 mlsPVA (5% w / v) (13-23 kDa, 98% hydrolysis)400 mlsBovine Insulin (Lot # 86HO674)100 mgZElan094 (SEQ. ID NO: 48) 10 mg / 50 ml dH20

Preparation:[0112]1. Water was heated to near boiling, PVA was added to 5% w / v and the solution was stirred until cool (phase A).[0113]2. Acetone and ethanol were mixed to form the organic phase (phase B).[0114]3. PLGA was added to the acetone and ethanol (step 2) and dissolved by stirring (phase B).[0115]4. An IKA™ reactor vessel was set at 25° C. Phase A (step 1) was added into the reactor vessel and stirred at 400 rpm.[...

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Abstract

The present invention relates to a novel membrane translocating full-length peptide sequence, fragment, motif, derivative, analog or peptidomimetic thereof (MTLPs), to nucleotide sequences coding therefor, and to compositions comprising a MTLP-active agent complex and a MTLP-active particle complex. The MTLP or the nucleotide sequence coding therefor enhance movement of the active agent or of the active particle across a lipid membrane. More particularly, the present invention relates to a MTLP-active agent complex and a MTLP-active particle complex, wherein the MTLP enhances uptake of the active agent into a cell, into or out of an intracellular compartment and across a cell layer. Methods of making and methods of using MTLPs also are included.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 09 / 671,089, filed Sep. 27, 2000, now U.S. Pat. No. 6,780,846, which claims the benefit of U.S. Provisional Application No. 60 / 156,246, filed on Sep. 27, 1999, the disclosures of which are incorporated by reference herein.FIELD OF THE INVENTION[0002]The present invention relates to peptides, which enhance uptake of a pharmaceutically active agent into a cell, into or out of an intracellular compartment, and across a cell layer. More particularly, the present invention relates to membrane translocating peptides, fragments, motifs, derivatives, analogs or peptidomimetics thereof and to the nucleotide sequences coding therefor, which enhance uptake of a pharmaceutically active agent into a cell, into or out of an intracellular compartment, and across a cell layer either directly or from a pharmaceutically active agent loaded particle.BACKGROUND OF THE INVENTION[0003]The epitheliu...

Claims

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Application Information

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IPC IPC(8): C07K1/00A61K9/127A61K9/51A61K38/28A61K47/48A61K48/00C07K7/08C07K14/50C07K14/665C12N15/88
CPCA61K9/1271A61K9/5153A61K38/28A61K47/48238A61K47/48338A61K48/00C07K7/08C07K14/50C07K14/665C12N15/88C07K2319/00A61K47/65A61K47/62
Inventor O'MAHONY, DANIEL J.LAMBKIN, IMELDA J.
Owner MERRION RES I
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